ABSTRACT Nearly half the men and women with HIV infection are racial/ethnic minorities living in the South. HIV infection remains a major public health problem despite the availability of treatments. The purpose of this proposal is to advance the knowledge of the consequences of HIV infection, with a focus on HIV-related comorbidities, by participating as a Clinical Research Sites (CRS) of the Multi-Center AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) Combined Cohort Study (MACS/WIHS-CCS). To meet this goal, Miami will provide expertise to lead important components of the CCS unified science agenda with protocol development and laboratory support to protocols and sub studies, as well as implementing the full CCS unified science agenda. To accomplish this, we will enroll and follow 500 men and women with HIV infection or at risk for HIV. We will enroll approximately 250 men reflective of the HIV epidemic in Miami, and follow men who have sex with men, bisexual men, and heterosexual men including men who are black or Hispanic representing a large minority proportion. As a current Southern WIHS site we will continue to follow the 149 women enrolled in WIHS who have HIV infection or at risk for HIV and are largely minority reflecting the Miami HIV epidemic. With availability of the CCS protocol, we will enroll additional 100 women from the community to reach a goal of approximately 250 women. The men and women enrolled will be consistent with protocol requirements of the MACS/WIHS consortium for new enrollments. Miami will continue its strong leadership, as we provided for the WIHS. Dr. Fischl as lead PI for this multiple PI proposal is the Vice Chair of the WIHS and has had an active role, along with colleagues, in the development of the unified science agenda, including the specific aims, frequency of core protocol visits, and timing of clinical tests, specimen collections, surveys, assessments and clinical tests. The Miami CRS will focus on protocols and sub studies in several innovative areas.1. Explore cardiovascular outcomes and HIV progression in the syndemic of HIV, tobacco, stimulant use, and depression, and investigate inflammatory biomarkers of cardiovascular disease risk and immune activation, including sex differences. 2. Explore the effects of the oral, female genital, and gut microbiome on the HIV reservoir and on exposure to antiretroviral therapy. 3. Evaluate comorbidities and effect of HIV persistence, inflammation and immune markers on comorbidity outcomes and plasma markers of inflammation, amyloid pathology and innate immune cell phenotypes on disease outcomes. 4. Examine the trajectories of vulnerabilities and resiliencies and relationship to HIV outcomes and comorbidities, and mechanisms by which psychosocial and behavioral predictors affect outcomes. 5. Examine the biological pathway whereby psychosocial factors and substance use may increase cardiovascular disease, impair neurocognitive function and contribute to HIV persistence. 5. Utilize developmental funds to support early stage and established investigators to develop innovative pilot studies. These findings will lead to improved understanding of HIV, treatment of HIV and guide future research.